Abstract Osteoarthritis (OA) is the leading cause of disability among older adults; in the absence of a cure, the need for primary preventive measures is essential. The objective of this R34 is to plan an assessor- blinded, 48-month, multi-center, randomized clinical trial designed to (a) establish intensive diet and exercise as an efficacious intervention for preventing incident symptomatic, radiographic knee OA; and (b) determine the cost-effectiveness of this non-pharmacologic intervention in preventing incident symptomatic, radiographic knee OA in high risk adult females. A substantial body of observational data suggests that interventions designed to attenuate joint loading and inflammation by exercise and weight loss show promise in preventing the onset of knee OA. Greater weight loss is associated with better cartilage health in the medial tibial compartment, including improvements in the quality (increased proteoglycan content) and quantity (attenuated cartilage thickness loss) of medial articular cartilage. Data also indicate that losing as little as 5 kg or 5% of baseline weight may result in as much as a 3-fold reduction in the risk of incident radiographic knee OA in obese women. Our approach of long-term intensive weight loss and exercise as a non- pharmacologic treatment for obese adults with knee OA recently tested in the IDEA trial elicited significant reductions in knee joint loads and pro-inflammatory cytokines, and improvements in self- efficacy. Taken together, these studies provide the clinical and mechanistic underpinning for our premise that dietary weight loss of ?10% of body weight combined with exercise will improve long-term clinical outcomes (pain and function) and prevent incident knee OA relative to control by reducing joint loads, lowering inflammation, and improving self-efficacy for weight loss in at-risk females. The FDA recognizes OA as a serious disease with an unmet medical need. The importance of OA disease prevention is evident because we presently have no effective disease-modifying interventions, there are substantial safety concerns associated with many pain medications, and there is no cure. This planning grant will provide support to conduct a model recruitment to test feasibility, establish a central IRB, refine the study protocol and retention and adherence plans, finalize a statistical analysis plan, and complete the manual of operating procedures. We will also establish and test a centralized reading protocol for all radiographs, develop training manuals for interventionists, and a detailed project timeline for the future clinical trial.